Prevalence of Anxiety Disorders

27

Lifetime Prevalence (%)

24 21 18 15 12 9 6 3 0 Any Anxiety Disorder Social Anxiety Disorder PTSD Generalized Anxiety Disorder Panic Disorder

Kessler et al. Arch Gen Psychiatry. 1995;52:1048. Kessler et al. Arch Gen Psychiatry. 1994;51:8.

Outcome of Panic Disorder at Long-Term Follow-up

Persistence of Panic attacks Phobic avoidance Functional impairment Rate (%) Range (%) 46 69 50 17-70 36-82 39-67
Roy-Byrne & Cowley, 1995

Pharmacopoeia for Anxiety Disorders

Antidepressants
Serotonin Selective Reuptake Inhibitors (SSRIs) Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Atypical Antidepressants Tricyclic Antidepressants (TCAs) Monoamine Oxidase Inhibitors (MAOIs)

Benzodiazepines

Other Agents
Azaspirones Beta blockers Anticonvulsants Other strategies

Serotonin Selective Reuptake Inhibitors

Fluoxetine (Prozac), 20-80 mg/d
Initiate with 5-10 mg/d

Sertraline (Zoloft), 50-200 mg/d

Initiate with 25-50 mg/d

Paroxetine (Paxil), 20-50 mg/d

Initiate with 10mg/d

Fluvoxamine (Luvox), 50-300 mg/d

Initiate with 25 mg/d

Citalopram (Celexa) - Initiate with 10-20 mg/d Start low to minimize anxiety Adjunctive BZD, beta blocker

Serotonin Selective Reuptake Inhibitors (cont)

Typical SSRI side effects:
GI distress, jitteriness, headaches, sleep disturbance, sexual disturbance

Clomipramine (Anafranil), 25-250 mg/d

Initiate with 25 mg/d

Efficacy: PDAG, PTSD, SP, OCD, GAD

Sertraline In Comorbid PTSD And Alcoholism

Pre-treatment Post-treatment 60 140

40 IES score 20 70 Standard drinks/week

0 IES Alcohol use

Brady et al. J Clin Psychiatry. 1995;56:502.

Discontinuation of Treatment for Anxiety Disorders

Withdrawal/rebound more common with Bzd than other anxiolytic treatment Relapse: a significant problem across treatments. Many patients require maintenance therapy Bzd abuse is rare in non-predisposed individuals Clinical decision: balance comfort/compliance/ comorbidity during maintenance treatment with discontinuation-associated difficulties

Strategies for Anxiolytic Discontinuation

Slow taper Switch to longer-acting agent for taper Cognitive-Behavioral therapy Adjunctive
Antidepressant Anticonvulsant ?clonidine, ?beta blockers, ? buspirone

Serotonin-Norepinephrine Reuptake Inhibitor

Venlafaxine-XR (Effexor-XR) 75-300 mg/d
Initiate with 37.5 mg/d

Indicated for GAD; effective for panic disorder, social phobia, PTSD, OCD Typical side effects
GI distress, jitteriness, headaches, sexual disturbance

Atypical Antidepressants
Nefazadone (300-500 mg/d) 5-HT reuptake inhibitor 5-HT2 antagonist Initiate with 50 mg bid Mirtazapine Limited experience to date in anxiety disorders

Atypical Antidepressants (cont.)

Bupropion
Based on limited data, considered less effective for panic and other anxiety disorders, but reports suggestive of efficacy for
panic disorder social anxiety disorder PTSD

Trazodone
Based on limited data, considered less effective for panic and other anxiety disorders

Tricyclic Antidepressants
Imipramine (Tofranil) Nortriptyline (Pamelor) Desipramine (Norpramin) Amitriptyline (Elavil) Doxepin (Sinequan)

Effective in anxiety with or without comorbid depression Recommended dosage 2.25 mg/kg/d Imipramine or its equivalent for panic Initial anxiety worsening (Initiate with test dose, e.g. 10 mg/d IMI)

Tricyclic Antidepressants (cont)

Typical TCA side effects anticholinergic effects (dry mouth, blurred vision, constipation) orthostatic hypotension cardiac conduction disturbance weight gain sexual dysfunction Lethal in overdose Weight gain and sedation often become increasingly problematic over time Efficacy: PDAG, GAD, PTSD

Monoamine Oxidase Inhibitors

Phenelzine (Nardil) 45-90 mg/d Tranylcypromine (Parnate) 30-60 mg/d Isocarboxacid (Marplan) 10-30 mg/d Initial worsening of anxiety is unusual Side effects: light-headedness, neurological symptoms, weight gain, sexual dysfunction, edema Dietary restrictions/Hypertensive crisis; cheese reaction Risk of lethal overdose and toxicity Generally reserved for refractory cases Efficacy: PDAG, SP, OCD, PTSD

Benzodiazepines
Potency was considered critical determinant of anti-panic efficacy
Alprazolam (Xanax) Clonazepam (Klonopin) +/- Lorazepam (Ativan)

But comparable doses of diazepam as effective as alprazolam All benzodiazepines effective for generalized anxiety

Potential Benefits of Benzodiazepine Therapy

Effective Short latency of therapeutic onset Well tolerated Rapid dose adjustment feasible Can be used prn for situational anxiety

Potential Drawbacks of Benzodiazepine Therapy

Initial sedation Discontinuation difficulties Potential for abuse in substance abusers Not effective for comorbid depression

Alprazolam
Effective as AD in panic Advantages: rapid onset of effect, lacks typical AD side effects Disadvantages: short duration of effect (i.e., multiple dosing, interdose rebound), discontinuation syndromes, early relapse, abuse potential, disinhibition Dosing: anticipate initial sedation (tachyphylaxis usually develops). Range: 2-10 mg/d (4-6 mg/d usual) (QID dosing)

Clonazepam
Labeled as anticonvulsant As effective as alprazolam for panic; issue of potency for antipanic efficacy Advantages: Pharmacokinetic: longer duration of effect results in less frequent dosing, interdose symptoms, early relapse, or acute withdrawal symptoms. Slower onset of effect diminishes abuse potential Disadvantages: Depression not more frequent than with other Bzds; disinhibition, headaches Dosing: anticipate initial sedation (initiate at 0.25-0.5 mg qhs) Range: 1-5 mg/d (BID dosing)

Combining Antidepressants with Benzodiazepines

Provides rapid anxiolysis during antidepressant lag Decreases early anxiety associated with initiation of antidepressant Treats residual anxiety wtih antidepressant treatment Prevents and treats depression on benzodiazepines

End-Point (LVCF) Analysis of Panic Disorder Severity Scale Scores for Each Group
2.5
*
Paroxetine + Placebo Paroxetine + Clonazepam Paroxetine + Clonazepame w/taper

2
Average PDSS scores

1.5

* *

0.5
Clonazepam Taper Phase

0
Week 00 Week 01 Week 02 Week 03 Week 04 Week 05 Week 06 Week 07 Week 08 Week 09 Week 10 Week 12

* Together the Clonazepam groups differ from the Placebo group at p< .05 Clonazepam groups differ from each other at p<.05

Pollack, et al 2001

Buspirone
Non-benzodiazepine anxiolytic Non-sedating, muscle relaxant, anticonvulsant Effects on serotonin and dopamine receptors Indicated for GAD; weak antidepressant effects Useful as SSRI augmentation for panic, social phobia, depression, sexual dysfunction Dosing: 30-60 mg/d

Beta Blockers
Decrease autonomic arousal May be useful as adjunct for somatic symptoms of panic and GAD but not as primary treatment Useful for non-generalized social phobia, performance anxiety subtype Propranolol 10-60 mg/d; Atenolol 50-150 mg/d

Anticonvulsants
Valproate and gabapentin effective for nonictal panic Gabapentin effective for social phobia Gabapentin (600-5400 mg/d) used as alternative to benzodiazepine Valproate, Carbamazepine, Gabapentin, Topiramate and Lamotrigine for PTSD

Strategies for Refractory Anxiety Disorder

Maximize dose Combine antidepressant and benzodiazepine Administer cognitive-behavioral therapy Attend to psychosocial issues

Strategies for Refractory Anxiety Disorders

Augmentation
Anticonvulsants
Gabapentin Valproate Topiramate

Combined SSRI/TCA Alternative antidepressant

Clomipramine MAOI

Beta blocker Other Buspirone Inositol Clonidine/Guanfacine Kava-kava Pindolol Atypical neuroleptics Dopaminergic agonists
(e.g., Ropinirole) for social phobia

Cyproheptadine

Cognitive-Behavioral Therapy for Anxiety Disorders

CBT useful alone or in combination with medication for
Refractory symptoms Persistent cognitive factors, behavioral patterns and anxiety sensitivity Comorbid conditions Early intervention for PTSD prophylaxis

CBT may be provided by therapist or selfadministered (TherapyWorks manuals 800-2280752///http://www.psychcorp.com)

CBT may facilitate medication discontinuation

.

Continuation Phase Outcome with Sertraline Treatment of PTSD Based on Acute Phase Response Category
Acute Phase Responder Status Continuation Phase Responder Status

Acute Phase Responders

Sustained Response
8%

92%

Lost response

Acute Phase Non-responders

Converted to responder 54%

Continued non-response
46%

0%

20%

40%

60%

80%

100%

Responder = > 30% decrease CAPS and CGI-S = 1 or 2

Londborg et al. J Clin Psychiatry, in press.

Long-Term Treatment Of GAD

Need to treat long-term
Full relapse in approximately 25% of patients 1 month after stopping treatment 60%-80% relapse within 1st year after stopping treatment
Hales et al. J Clin Psychiatry. 1997;58(suppl 3):76. Rickels et al. J Clin Psychopharmacol. 1990;10(3 suppl):101S.

Effect Of Venlafaxine On Total HAM-A Scores

0 -2 -4 -6 Change In -8 Mean HAM-A Total Score -10 -12 -14 Placebo (N=123) Venlafaxine XR (N=115)

-16
-18 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Week Of Treatment
P<.001 for venlafaxine XR vs placebo for all study weeks except week 1 (.003), week 4 (.002), and week 20 (.007) Venlafaxine XR doses: 75 to 225 mg/d. Gelenberg et al. JAMA. 2000;283:3082.

Paroxetine Long-Term GAD Treatment % Remission

Phase I: Single-Blind Phase II: Double-Blind Placebo (N=274) Paroxetine (N=285) * * * *

80
70 60 Patients 50 (%) 40 30 20 10 0

Paroxetine 20-50 mg (N=599 responders) Randomization

* P<.01 vs placebo. Remission = HAM-A 7; LOCF dataset. GlaxoSmithKline data on file, 2001.

8 12 Week

16

20

24

28

32

Discontinuation of Treatment for Anxiety Disorders

Withdrawal/rebound more common with Bzd than other anxiolytic treatment Relapse: a significant problem across treatments. Many patients require maintenance therapy Bzd abuse is rare in non-predisposed individuals Clinical decision: balance comfort/compliance/ comorbidity during maintenance treatment with discontinuation-associated difficulties

Strategies for Anxiolytic Discontinuation

Slow taper Switch to longer-acting agent for taper Cognitive-Behavioral therapy Adjunctive
Antidepressant Anticonvulsant ?clonidine, ?beta blockers, ? buspirone